Terlipressin Treatment Is Associated With Reversal of Hepatorenal Syndrome in Patients With Alcoholic Hepatitis
Authors: Samuel H. Sigal, Arun J. Sanyal, R. Todd Frederick, Ethan M. Weinberg, S. Chris Pappas, Khurram Jamil
Journal: Clinical Gastroenterology and Hepatology (2023)

Alcoholic hepatitis (AH) develops after extended periods of excessive alcohol consumption and frequently leads to cirrhosis and liver failure.1Hosseini N. et al.Alcohol and Alcoholism. 2019; 54: 408-416Crossref PubMed Scopus (65) Google Scholar Patients with severe AH—defined by a Maddrey discriminant function (MDF) score of ≥32—often develop acute kidney injury (AKI), which is associated with dismal outcomes. In a study of 103 patients with AH, 28% developed AKI, and 3-month survival was reduced to 35% vs 93% for those without AKI.2Altamirano J. et al.Clin Gastroenterol Hepatol. 2012; 10: 65-71Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Vasoconstrictor therapy plus albumin is an effective treatment for hepatorenal syndrome (HRS).3Simonetto D.A. et al.BMJ. 2020; 370: m2687Crossref PubMed Scopus (72) Google Scholar Terlipressin (a synthetic long-acting vasopressin analog) plus albumin was associated with higher rates of HRS reversal—defined as at least 1 serum creatinine measurement of ≤1.5 mg/dL while on treatment—and improved renal function vs placebo in 3 phase III randomized, double-blind, placebo-controlled studies (A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III Study of Intravenous Terlipressin in Patients With Hepatorenal Syndrome Type 1 (OT-0401), NCT00089570; A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study), NCT01143246; and A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1 (The CONFIRM Study), NCT02770716).4Boyer T.D. et al.Gastroenterology. 2016; 150: 1579-1589Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 5Sanyal A.J. et al.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 6Wong F. et al.N Engl J Med. 2021; 384818828Crossref Scopus (86) Google Scholar Terlipressin is the first therapy approved by the US Food and Drug Administration for the treatment of adult patients with HRS.7Bedminster N.J. TERLIVAZ (terlipressin)Mallinckrodt Pharmaceuticals. 2022; Google Scholar Because of the devastating impact of HRS on mortality in patients with severe AH, determination of terlipressin efficacy in patients with this condition is important. In this retrospective analysis of data from A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III Study of Intravenous Terlipressin in Patients With Hepatorenal Syndrome Type 1 (OT-0401), A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study), and A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1 (The CONFIRM Study),4Boyer T.D. et al.Gastroenterology. 2016; 150: 1579-1589Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 5Sanyal A.J. et al.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 6Wong F. et al.N Engl J Med. 2021; 384818828Crossref Scopus (86) Google Scholar we report the effect of terlipressin on clinical outcomes in the subset of patients with AH in terms of HRS response, survival, and relationship with MDF score. In the pooled intent-to-treat population (N = 608), 205 (33.7%) patients were diagnosed with AH (terlipressin, n = 121; placebo, n = 84) based on investigator assessment. When evaluated in the entire intent-to-treat population, AH was not a significant variable in the logistic regression analysis of baseline factors associated with HRS reversal in the terlipressin (odds ratio, 1.38; P = .169) or placebo group (odds ratio, 0.69; P = .320). Consequently, the presence of AH did not affect treatment response negatively and should not preclude the use of terlipressin for the treatment of HRS in this patient population. In the AH subpopulation, baseline patient clinical characteristics were similar across treatment groups. Acute-on-chronic liver failure grades 2−3 were observed in 70.2% and 72.6% of patients in the terlipressin and placebo groups, respectively. The mean Model for End-Stage Liver Disease score was 35.5 in the terlipressin group and 35.0 in the placebo group, and 17.4% of patients in the terlipressin group vs 11.9% of patients in the placebo group had received prior steroid therapy. Significantly more patients with AH achieved HRS reversal when treated with terlipressin compared with placebo (38.0% vs 13.1%; P < .001) (Figure 1A). Treatment effect was durable: more patients in the terlipressin vs placebo group were alive, renal replacement therapy (RRT)-free, and maintained HRS reversal on day 30 (33.9% vs 10.7%; P < .001). The overall survival (OS) benefit among terlipressin-treated patients with AH showed a favorable trend, but did not reach statistical significance vs placebo (median OS, 51 vs 30 d; P = .192) (Supplementary Figure 1A). The safety profile was comparable between treatment groups: serious adverse events of any grade occurred in 68.6% and 75.6% of patients in the terlipressin and placebo groups, respectively; respiratory failure was observed more frequently in the terlipressin vs placebo group (9.1% vs 3.7%, respectively; P = .134). The incidence of serious adverse events in the AH population was similar to previously published data for the entire population.6Wong F. et al.N Engl J Med. 2021; 384818828Crossref Scopus (86) Google Scholar Given the poor outcomes among patients with HRS requiring RRT,8Ginès P. et al.Nat Rev Dis Primers. 2018; 4: 23Crossref PubMed Scopus (53) Google Scholar,9Allegretti A.S. et al.Clin J Am Soc Nephrol. 2018; 13: 16-25Crossref PubMed Scopus (59) Google Scholar we considered RRT with or without liver transplantation (LT) and death to be adverse outcomes. These combined adverse clinical outcomes occurred less frequently in patients who had received terlipressin at all time points: 57.0% vs 66.7% on day 30, 62.8% vs 73.8% on day 60, and 64.5% vs 73.8% on day 90, in the terlipressin and placebo groups, respectively; however, the difference did not reach statistical significance (Figure 1B). Severe AH (MDF score of greater than 32) carries up to a 60% risk of short-term mortality, while low MDF scores (less than 32) predict a more favorable prognosis.1Hosseini N. et al.Alcohol and Alcoholism. 2019; 54: 408-416Crossref PubMed Scopus (65) Google Scholar Unlike the Model for End-Stage Liver Disease score, the MDF score does not take into consideration underlying renal dysfunction. Importantly, in our analysis—despite a small cohort—placebo-treated patients with an MDF score lower than 32 experienced inferior survival compared with terlipressin-treated patients, thereby highlighting the importance of recognizing and treating renal dysfunction in patients with AH. OS was significantly shorter in the placebo group vs the terlipressin group (P = .027); 100% (5 of 5) of patients who received terlipressin were alive on day 90 vs 33.3% (3 of 9) of those who received placebo (Supplementary Table 1 and Supplementary Figure 1B). A similar trend was observed among patients with severe AH with an MDF score of 32 to 54: the median OS was numerically shorter when patients were treated with placebo vs terlipressin (P = .10). In the subpopulation of patients with an MDF score greater than 54, OS was similar in both treatment groups (Supplementary Table 1 and Supplementary Figure 1B). Limitations of this study include AH classification status based on a clinical determination by the investigator. Furthermore, because of the post hoc nature of the analysis, the calculation of the MDF score required the use of an estimated prothrombin time because only information on the international normalized ratio was collected prospectively. Finally, the sample size was small in some of the analyses, which might have affected the significance of the results. There is a high unmet medical need for patients with AH and HRS—a condition that preferentially affects socioeconomically disadvantaged individuals with a high hospital mortality rate.1Hosseini N. et al.Alcohol and Alcoholism. 2019; 54: 408-416Crossref PubMed Scopus (65) Google Scholar,10Crabb D.W. et al.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (299) Google Scholar Clear evidence for corticosteroid therapy in patients with AH and HRS is not available.10Crabb D.W. et al.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (299) Google Scholar LT remains the only definitive treatment for patients with HRS.8Ginès P. et al.Nat Rev Dis Primers. 2018; 4: 23Crossref PubMed Scopus (53) Google Scholar Survival of a patient requiring RRT without LT is extremely limited.9Allegretti A.S. et al.Clin J Am Soc Nephrol. 2018; 13: 16-25Crossref PubMed Scopus (59) Google Scholar Although LT for carefully selected patients with AH increasingly is considered, the majority are not eligible.1Hosseini N. et al.Alcohol and Alcoholism. 2019; 54: 408-416Crossref PubMed Scopus (65) Google Scholar,10Crabb D.W. et al.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (299) Google Scholar Consequently, patients with AH and HRS have few therapeutic options and often are denied both LT and RRT.1Hosseini N. et al.Alcohol and Alcoholism. 2019; 54: 408-416Crossref PubMed Scopus (65) Google Scholar,9Allegretti A.S. et al.Clin J Am Soc Nephrol. 2018; 13: 16-25Crossref PubMed Scopus (59) Google Scholar,10Crabb D.W. et al.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (299) Google Scholar The demonstrated beneficial effect of terlipressin on HRS reversal in patients with AH and HRS, and the absence of an adverse effect of AH on the safety of terlipressin therapy, are important findings. Effective treatment to improve kidney function is essential to allow these patients time to recover or to achieve LT eligibility.1Hosseini N. et al.Alcohol and Alcoholism. 2019; 54: 408-416Crossref PubMed Scopus (65) Google Scholar,9Allegretti A.S. et al.Clin J Am Soc Nephrol. 2018; 13: 16-25Crossref PubMed Scopus (59) Google Scholar,10Crabb D.W. et al.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (299) Google Scholar Our data indicate that a diagnosis of AH should not preclude treatment with terlipressin, which could provide a bridge to LT or recovery from AH. A retrospective analysis of pooled data from patients with AH from the OT-0401, REVERSE, and CONFIRM randomized, placebo-controlled, phase III studies was performed.1Boyer T.D. et al.Gastroenterology. 2016; 150: 1579-1589Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 2Sanyal A.J. et al.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar, 3Wong F. et al.N Engl J Med. 2021; 384: 818-828Crossref PubMed Scopus (105) Google Scholar Eligible patients were adults with HRS type 1 diagnosed using standard criteria before the adoption of the 2015 International Club of Ascites HRS-AKI criteria.4Angeli P. et al.J Hepatol. 2015; 62: 968-974Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar Terlipressin or placebo was administered with recommended concomitant albumin (CONFIRM, 1 g/kg body weight to <100 g followed by 20–40 g/d; REVERSE, 20–40 g/d; OT-0401, 100 g on day 1 followed by 25 g/d).1Boyer T.D. et al.Gastroenterology. 2016; 150: 1579-1589Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 2Sanyal A.J. et al.Gastroenterology. 2008; 134: 1360-1368Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar, 3Wong F. et al.N Engl J Med. 2021; 384: 818-828Crossref PubMed Scopus (105) Google Scholar The presence of AH was based on clinical assessment by the local investigator; confirmation via a liver biopsy was not performed. RRT included both intermittent hemodialysis and continuous RRT. The MDF score was calculated by adding the baseline bilirubin (mg/dL) to 4.6 times the (estimated prothrombin time − 13). Because prothrombin time was not collected prospectively, it was estimated by multiplying the baseline international normalized ratio by an assigned control value of 13 seconds (based on the normal prothrombin time range). HRS reversal was defined as more than 1 serum creatinine measurement of less than 1.5 mg/dL while on treatment for up to 24 hours after the last dose; serum creatinine values after RRT and LT were excluded. Adverse clinical outcomes were defined as death, the need for RRT in the absence of LT, and peritransplant RRT; no need for RRT—with or without LT—was considered a positive outcome. Clinical outcomes were recorded on days 30, 60, and 90 after the last dose of the study drug. Transplant or death outcomes were counted once, whichever event occurred first. Results for each prespecified time point were cumulative. OS was analyzed by treatment up to day 90 in all patients with AH and based on MDF scores. For numeric data (summarized as a percentage), a Fisher exact test was used if the number of events per comparator was fewer than 5; otherwise, a chi-squared test was used. The association of AH at baseline with HRS reversal was assessed by a univariable regression model; associated P values were calculated from a Wald test. Survival estimates were assessed using the Kaplan–Meier method and compared by a 2-sample log-rank test. Analyses were conducted using SAS version 9.4 (Cary, NC).Supplementary Table 1Overall Survival for Up to 90 Days by Treatment Group in Patients With AH and HRS Overall and by MDF Score (Pooled ITT Population)AllMDF score <32MDF score 32–54MDF score >54Terli (n = 121)Pbo (n = 84)PaP values comparing the survival estimates were calculated from a 2-sample log-rank test.Terli (n = 5)Pbo (n = 9)PaP values comparing the survival estimates were calculated from a 2-sample log-rank test.Terli (n = 13)Pbo (n = 9)PaP values comparing the survival estimates were calculated from a 2-sample log-rank test.Terli (n = 94)Pbo (n = 60)PaP values comparing the survival estimates were calculated from a 2-sample log-rank test.OS up to 90 days.192.027.100.814Median OS (days)5130NR28NR222933Alive at day 90 visit (n, %)57 (47.1)33 (39.3)5 (100.0)3 (33.3)8 (61.5)3 (33.3)39 (41.5)25 (41.7)NOTE. The MDF score was calculated as follows: baseline bilirubin (mg/dL) + (4.6 × [estimated prothrombin time–13]). The estimated prothrombin time was calculated by multiplying the baseline international normalized ratio by 13. Data were pooled from A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III Study of Intravenous Terlipressin in Patients With Hepatorenal Syndrome Type 1 (OT-0401), A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study), and A Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1 (The CONFIRM Study).AH, alcoholic hepatitis; HRS, hepatorenal syndrome; ITT, intent-to-treat; MDF, Maddrey discriminant function; NR, not reached; OS, overall survival; Pbo, placebo; Terli, terlipressin.a P values comparing the survival estimates were calculated from a 2-sample log-rank test. Open table in a new tab NOTE. The MDF score was calculated as follows: baseline bilirubin (mg/dL) + (4.6 × [estimated prothrombin time–13]). The estimated prothrombin time was calculated by multiplying the baseline international normalized ratio by 13. Data were pooled from A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III Study of Intravenous Terlipressin in Patients With Hepatorenal Syndrome Type 1 (OT-0401), A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study), and A Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1 (The CONFIRM Study). AH, alcoholic hepatitis; HRS, hepatorenal syndrome; ITT, intent-to-treat; MDF, Maddrey discriminant function; NR, not reached; OS, overall survival; Pbo, placebo; Terli, terlipressin.